synthesis and biological evaluation of 3-aryl-quinoxaline-2-carbonitrile 1,4-di-n-oxide derivatives as hypoxic selective anti-tumor agents合成和生物评价3-aryl-quinoxaline-2-carbonitrile 1,4-di-n-oxide衍生品作为缺氧有选择性的抗肿瘤药物.pdf

Molecules 2012, 17, 9683-9696; doi:10.3390/molecule OPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Article Synthesis and Biological Evaluation of 3-Aryl-quinoxaline-2- carbonitrile 1,4-Di-N-oxide Derivatives as Hypoxic Selective Anti-tumor Agents Yunzhen Hu 1,2, Qing Xia 1, Shihao Shangguan 1, Xiaowen Liu 3, Yongzhou Hu 1 and Rong Sheng 1,* 1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, Hangzhou 310058, China 2 Department of Pharmacy, the First Affiliated Hospital of college of Medicine, Zhejiang University, Hangzhou 310006, China 3 Institute of Pharmacology Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China * Author to whom correspondence should be addressed; E-Mail: shengr@; Tel./Fax: +86-571-8820-8458. Received: 6 July 2012; in revised form: 1 August 2012 / Accepted: 2 August 2012 / Published: 13 August 2012 Abstract: A series of 3-aryl-2-quinoxaline-carbonitrile 1,4-di-N-oxide derivatives were designed, synthesized and evaluated for hypoxic and normoxic cytotoxic activity against human SMMC-7721, K562, KB, A549 and PC-3 cell lines. Many of these new compounds displayed more potent hypoxic cytotoxic activity compared with TX-402 and TPZ in the tumor cells based evaluation, which confirmed our hypothesis that the replacement of the 3-amine with the substituted aryl ring of TX-402 increases the hypoxic anti-tumor activity. The preliminary SAR revealed that 3-chloro was a